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PubMed2006

Solid-phase synthesis of biologically interesting compounds containing hydroxamic acid moiety.

Chemical strategies developed for the solid-phase synthesis of hydroxamates are divided into four groups: (i) the traditional synthesis of hydroxamates via cleavage of resin-bound esters by hydroxylamine and its derivatives, (ii) introduction of hydroxamic acid moiety on the resin-bound precursor, (iii) transformation of polymer-supported hydroxylamine, attached to a solid supported linker either by oxygen (O-linking strategy) or by nitrogen (N-linking strategy), and (iv) synthesis of N-alkyl hydroxamates. The scope and limitation of individual approaches are discussed.

Arylsulfonates↗
PubMed1980

Jack bean urease (EC 3.5.1.5). IV. The molecular size and the mechanism of inhibition by hydroxamic acids. Spectrophotometric titration of enzymes with reversible inhibitors.

Kinetic, spectral, and other studies establish that hydroxamic acids bind reversibly to active-site nickel ion in jack bean urease. Equilibrium ultracentrifugation studies establish that the molecular weight of native urease is 590 000 +/- 30 000 while that of the subunit formed in 6 M guanidinium chloride in the presence of beta-mercaptoethanol is approximately 95 000. Essentially the same subunit molecular weight (approximately 93 000) is found by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate, subsequent to denaturation in a guanidinium chloride - beta-mercaptoethanol system at various temperatures. Coupled with an equivalent weight of 96 600 for binding of the inhibitors acetohydroxamic acid and phosphoramidate, these results establish securely that urease is a hexamer with one active site per 96 600-dalton subunit. Consistent values for the equivalent weight are obtained by a routine spectrophotometric titration of the active site of freshly prepared urease with trans-cinnamoylhydroxamic acid. General equations are derived which describe spectrophotometric titrations of binding sites of any enzyme with a reversible inhibitor. These equations allow the evaluation of the difference spectrum of the protein-inhibitor complex even when the binding sites cannot readily be saturated with the inhibitor or vice versa.

Amino Acids↗
PubMed1984

'In vivo' amplification of biological activity of tetragastrin by amino acid hydroxamates.

Rat blood was shown to contain an aminopeptidase which rapidly hydrolyses short peptides containing an aromatic amino acid as N-terminal residue. Using tetragastrin (Trp-Met-Asp-PheNH2) as substrate, we showed that some amino acid hydroxamates inhibit rat aminopeptidase activity 'in vitro' in the following order: HTrpNHOH greater than HPheNHOH much greater than HAlaNHOH. The same hydroxamates markedly enhanced the biological activity of tetragastrin 'in vivo'. The amplification of the secretory effect, correlated with the amount of the hydroxamate used, strongly suggests that these compounds can stabilize a number of active peptides in vivo by inhibiting their proteolytic degradation.

Amino Acids↗
PubMed2006

In vitro and in vivo histone deacetylase inhibitor therapy with suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer.

OBJECTIVE: To determine effects of suberoylanilide hydroxamic acid (SAHA) with and without paclitaxel in ovarian cancer cells and a nude mouse model. METHODS: Cell viability and apoptosis of ovarian cancer cells (2774) were measured following exposure to control, SAHA, paclitaxel, or SAHA in combination with paclitaxel. Nude mice were injected intraperitoneally (IP) with cancer cells and then groups received variable SAHA doses (25-100 mg/kg/day). In a second experiment, mice were inoculated with cancer and treated IP with vehicle injection, SAHA, paclitaxel, paclitaxel followed by SAHA, or SAHA followed by paclitaxel. Survival, tumor weight, and ascites were evaluated. RESULTS: SAHA decreased viability and increased apoptosis similarly to paclitaxel, but the combination was not statistically significantly different from the single agents. The only significant difference in the SAHA alone mouse study was decreased survival in the 50 mg/kg/daily group. In the combination groups, SAHA followed by paclitaxel, paclitaxel alone, and paclitaxel followed by SAHA improved survival compared with control (p=0.0358, 0.0006, and 0.0001), but SAHA alone did not (p=0.524). The paclitaxel followed by SAHA group had improved survival compared to SAHA followed by paclitaxel (p=0.0002) but not compared to paclitaxel alone (p=0.166). CONCLUSIONS: In vitro, SAHA alone decreased viability and increased apoptosis similarly to paclitaxel. In vivo, paclitaxel followed by SAHA and paclitaxel alone increased survival compared with SAHA alone or SAHA followed by paclitaxel. This suggests adding SAHA to ovarian cancer chemotherapy could increase efficacy and that sequencing of agents is important.

Animals↗
PubMed2000

Suberoylanilide hydroxamic acid as a potential therapeutic agent for human breast cancer treatment.

BACKGROUND: Suberoylanilide hydroxamic acid (SAHA) is a prototype of the newly developed, second-generation, hybrid polar compounds. It is a novel histone deacetylase inhibitor with high potency for inducing cell differentiation of cultured murine erythroleukemia cells. Studies with SAHA have primarily been performed with hematopoietic tumor cells. Here we extent these studies with SAHA to human breast cancer cell lines in an attempt to find better therapeutic agents for breast cancer treatment. MATERIALS AND METHODS: Human breast cancer cell lines, MCF7, MDA-MB-231, and MDA-MB-435, as well as normal cells, including the normal breast epithelial cell line MCF-10A, and fibroblasts, were treated with SAHA. Cells assayed for cell survival by using trypan blue exclusion assay, colony formation assay, and cell cycle and apoptosis analysis. The effects of SAHA on cell cycle and apoptosis regulatory proteins were examined by Western blots analysis. The identification of additional target genes was carried out by differential display (DD) and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: SAHA inhibited clonogenic growth of MCF7, MDA-MB-231, and MDA-MB-435 breast cancer cells. These cells were more sensitive to SAHA-mediated cytotoxic effects than normal breast epithelial cells and fibroblasts. The cytotoxic effects of SAHA on breast cancer cells were manifested by G1 and G2/M cell cycle arrest and eventual apoptosis. The pan-caspase inhibitor, Z-VAD.fmk, blocked SAHA-induced cell death, DNA laddering, and cleavage of poly(ADP-ribose) polymerase, indicating the involvement of caspases in SAHA-mediated apoptosis. In addition, SAHA modulated cell cycle and apoptosis regulatory proteins. For example, cyclin-dependent kinase (CDK) inhibitors p21WAF1/Cip1 and p27Kip1 were induced, and retinoblastoma protein pRb was hypophosphorylated. Moreover, SAHA induced several genes associated with differentiation and/ or growth inhibition. These genes encode gelsolin, isopentenyl-diphosphate delta isomerase (IDI1), and 1,25-dihydroxyvitamin D-3 up-regulated protein 1 (VDUP1), the last two of which were identified by DD. Induction of these genes may contribute to SAHA-mediated pro-differentiating and antiproliferative effects. CONCLUSIONS: SAHA induced growth inhibition, cell cycle arrest, and eventual apoptosis in human breast cancer cells, possibly by modulating cell cycle and apoptosis regulatory proteins, such as CDK inhibitors p21 and p27, pRb, and other differentiation and/or growth inhibition-associated genes, including gelsolin, IDI1 and VDUP1. This, together with the low toxicity in normal cells, suggests that SAHA might have therapeutic potential for the treatment of human breast cancers.

Antineoplastic Agents↗
PubMed2004

Liquid/air interfacial structure of alcohol-octyl hydroxamic acid mixtures: a study by sum-frequency spectroscopy.

The molecular structure of the liquid/air interfaces of 1-octanol, 1-decanol, n-decane and the branched decyl alcohol EXXAL 10 has been studied by sum-frequency spectroscopy (SFS) in the C-H stretching vibrational region. The data suggest that the interfaces consist of ordered molecules with closely packed alkyl tails, in close to all-trans conformation with some gauche defects. The degree of surface ordering for the branched alcohol is much higher than for octanol and decanol. When octyl hydroxamic acid (OHA) is dissolved in 1-octanol it increases the gauche conformational defects in the interfacial chains, possibly due to mixing with the surface alcohol molecules and disrupting their ordering. In contrast, we suggest that when octyl hydroxamic acid is dissolved in EXXAL 10, the surface ordering of the alcohol chains does not change. We put forward the hypothesis that the appearance of new bands, belonging to the asymmetric methylene group vibrations and to the asymmetric methyl modes in the SF spectra of the mixture suggests that the surface OHA molecules are arranged with their hydrocarbon tails tilted very close to the interface.

1-Octanol↗
PubMed2003

A comparative QSAR study on carbonic anhydrase and matrix metalloproteinase inhibition by sulfonylated amino acid hydroxamates.

A quantitative structure-activity relationship (QSAR) study is made on the inhibition of a few isozymes of carbonic anhydrase (CA) and some matrix metalloproteinases (MMPs), both zinc containing families of enzymes, by sulfonylated amino acid hydroxamates. For both enzymes, the inhibition potency of the hydroxamates is found to be well correlated with Kier's first-order valence molecular connectivity index 1chi(v) of the molecule and electrotopological state indices of some atoms. From the results, it is suggested that while hydroxamate-CA binding may involve mostly polar interactions, hydroxamate-MMP and hydroxamate-ChC (ChC: Clostridium histolyticum collagenase, another zinc enzyme related to MMPs) bindings may involve some hydrophobic interactions. Both MMPs and ChC also possess some electronic sites of exactly opposite nature to the corresponding sites in CAs. A group such as C6F5 present in the sulfonyl moiety is shown to be advantageous in both CA and MMP (also ChC) inhibitions, which is supposed to be due to the interaction of this group with Zn2+ ion present in the catalytic site of both families of enzymes.

Carbonic Anhydrase Inhibitors↗
PubMed2000

Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo.

Suberoylanilide hydroxamic acid (SAHA) is the prototype of a family of hybrid polar compounds that induce growth arrest in transformed cells and show promise for the treatment of cancer. SAHA induces differentiation and/or apoptosis in certain transformed cells in culture and is a potent inhibitor of histone deacetylases. In this study, we examined the effects of SAHA on the growth of human prostate cancer cells in culture and on the growth of the CWR22 human prostate xenograft in nude mice. SAHA suppressed the growth of the LNCaP, PC-3, and TSU-Pr1 cell lines at micromolar concentrations (2.5-7.5 microM). SAHA induced dose-dependent cell death in the LNCaP cells. In mice with transplanted CWR222 human prostate tumors, SAHA (25, 50, and 100 mg/kg/day) caused significant suppression of tumor growth compared with mice receiving vehicle alone; treatment with 50 mg/kg/day resulted in a 97% reduction in the mean final tumor volume compared with controls. At this dose, there was no detectable toxicity as evaluated by weight gain and necropsy examination. Increased accumulation of acetylated core histones was detected in the CWR22 tumors within 6 h of SAHA administration. SAHA induced prostate-specific antigen mRNA expression in CWR22 prostate cancer cells, resulting in higher levels of serum prostate-specific antigen than predicted from tumor volume alone. The results suggest that hydroxamic acid-based hybrid polar compounds inhibit prostate cancer cell growth and may be useful, relatively nontoxic agents for the treatment of prostate carcinoma.

Animals↗
PubMed2002

Oxal hydroxamic acid derivatives with inhibitory activity against matrix metalloproteinases.

Several amines, amino acid derivatives and low molecular weight peptides containing an amide-bound oxal hydroxamic acid moiety have been synthesized and tested for their inhibitory effects towards native human gelatinase B (MMP-9) and the catalytic domains of the membrane type MT1-MMP (MMP-14) and of neutrophil collagenase (MMP-8). A number of these compounds exhibited considerable inhibitory activity against the tested metalloproteinases.

Amines↗
PubMed1984

The actions of the hydroxamic acid of gamma amino butyric acid on the isolated rabbit atria and jejunum.

The hydroxamic acid of gamma amino butyric acid (HAGABA) has been prepared and was studied in the isolated rabbit atria and jejunum. HAGABA did not interfere with the spontaneous contractile rhythm and frequency of the isolated atria except in large mM concentrations in the bath. HAGABA displayed a biphasic effect in the isolated jejunum, which manifested itself first as stimulation followed by inhibition with an increasing concentration in the bath. Bicuculline and HAGABA did not antagonize each other in the enteric nervous system, but rather an augmentation was observed.

Acetylcholine↗
PubMedDate not supplied

A novel hydroxamic acid compound, BMD188, demonstrates anti-prostate cancer effects by inducing apoptosis. I: In vitro studies.

BACKGROUND: Prostate cancer is the most frequently diagnosed malignancy in the Western countries. Apoptosis-targeted drug development could represent a specific and effective weapon against the disease (Tang and Porter, 32: 284-293, 1997). We previously demonstrated that the arachidonate 12-lipoxygenase and its metabolic products could function as survival factors for many solid tumors (Tang et al., Proc. Natl. Acad. Sci. USA 93: 5241-5246, 1996; Tang and Honn, J. Cell. Physiol. 172: 155-170, 1997). MATERIALS AND METHODS: In this study, we synthesized a series of novel cyclic hydroxamic acid compounds that demonstrated varying degrees of inhibitory effects on the arachidonate 12-lipoxygenase. Subsequently we studied the effects of these novel compounds on human prostate cancer cells. First, all these compounds were screened on androgen-independent PC3 adenocarcinoma cells. Second, based on the results (i.e., the LD50 values) of the primary, secondary and tertiary screening, lead compounds were determined. Third, the lead compounds were utilized to study their cytotoxic effects on various prostate cancer cells as well as several types of normal cells. Finally, the molecular nature of the cell death was thoroughly characterized and the potential mechanisms of cell death were determined. RESULTS: About 30% of the compounds screened induced a strong apoptotic death of androgen-independent prostate cancer cells, PC3, with an LD50 mostly at 10-20 microM. A lead compound, BMD188 [cis-1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one], was subsequently identified which inhibited the growth of PC3 cells with an LD50 at approximately 10 microM. Comparative studies indicated that BMD188 induced a more potent apoptotic response in PC3 cells than several conventional chemotherapeutic drugs. Furthermore, unlike the above drugs, BMD188 could induce 100% apoptosis in tumor cells. BMD188 also caused apoptosis of other types of prostate cancer cells including cells with multidrug resistance phenotype, independent of the androgen-dependence and p53 status. By contrast, BMD188 generally demonstrated 2-5 fold lower cytotoxicity towards several normal cell types including normal prostate epithelial cells. The growth inhibition by BMD188 was due to apoptosis induction as evidenced by DNA ladder formation, PARP [poly(ADP-ribose)polymerase] cleavage, and typical apoptotic morphology. BMD188-induced apoptosis does not depend on its inhibitory effects on lipoxygenase since target cells (i.e., PC3 and Du145) did not express the lipoxygenase mRNA and protein. In contrast, the apoptosis-inducing effect of BMD188 in PC3 cells could be significantly inhibited by serine protease inhibitors TPCK and TLCK as well as by caspase inhibitors DEVD and zVAD. The involvement of caspases in the apoptotic effects of BMD188 was further confirmed by the activation of caspase-3 (CPP32). In the accompanying paper, we show that BMD188 also inhibits the primary growth and local invasion of Du145 prostate cancer cells orthotopically implanted into the SCID or athymic nude mice. CONCLUSION: The data presented here suggest that these novel cyclic hydroxamic acid compounds, via induction of apoptotic death, may find potential clinical applications in the treatment of human prostate cancers.

Animals↗
PubMed2003

Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously.

PURPOSE: To evaluate the safety, pharmacokinetics, and biological activity of suberoylanilide hydroxamic acid (SAHA) administered by 2-h i.v. infusion in patients with advanced cancer. EXPERIMENTAL DESIGN: SAHA was administered for 3 days every 21 days in part A and 5 days for 1-3 weeks in part B. Dose escalation proceeded independently in patients with solid tumor and hematological malignancies (part B only). Pharmacokinetic studies were performed along with assessment of acetylated histones in peripheral blood mononuclear cells and tumor tissues. RESULTS: No dose-limiting toxicities were observed in 8 patients enrolled in part A (75, 150, 300, 600, and 900 mg/m(2)/day). Among 12 hematological and 17 solid tumor patients enrolled in part B (300, 600, and 900 mg/m(2)/day), therapy was delayed > or = 1 week for grade 3/4 leukopenia and/or thrombocytopenia in 2 of 5 hematological patients at 600 mg/m(2)/day x 5 days for 3 weeks. The maximal-tolerated dose was 300 mg/m(2)/day x 5 days for 3 weeks for hematological patients. One solid patient on 900 mg/m(2)/day x 5 days for 3 weeks developed acute respiratory distress and grade 3 hypotension. The cohort was expanded to 6 patients, and no additional dose-limiting toxicities were observed. Mean terminal half-life ranged from 21 to 58 min, and there was dose-proportional increase in area under the curve. An accumulation of acetylated histones in peripheral blood mononuclear cells up to 4 h postinfusion was observed at higher dose levels. Posttherapy tumor biopsies showed an accumulation of acetylated histones by immunohistochemistry. Four (2 lymphoma and 2 bladder) patients had objective tumor regression with clinical improvement in tumor related symptoms. CONCLUSIONS: Daily i.v. SAHA is well tolerated, inhibits the biological target in vivo, and has antitumor activity in solid and hematological tumors.

Acetylation↗
PubMed1995

Hydroxamic acids as potent inhibitors of endothelin-converting enzyme from human bronchiolar smooth muscle.

Hydroxamic acids 6a-h, derived from malonyl amino acids, and 25a-d, derived from succinyl amino acids, were synthesized as inhibitors of human bronchiolar smooth muscle endothelin-converting enzyme (HBSM ECE). Several unexpected side reactions were discovered, particularly in the synthesis of hydroxamates derived from succinates. In vitro evaluation against human bronchiolar ECE revealed that in all cases hydroxamates derived from malonate were more potent than hydroxamates derived from succinate. Isopropyl and isobutyl P1' side chains were suitable; omission of the P1' side chain seriously diminished potency. In the P2' position, several amino acids gave potent malonate-derived hydroxamate inhibitors (6b, d-h, IC50 = 0.2-6.8 nM), and beta-Ala provided an extremely potent inhibitor (6c, IC50 = 0.01 nM). C-terminus carboxylates are much more potent ECE inhibitors than the corresponding amides. Most of the hydroxamates were also potent inhibitors of thermolysin and neutral endopeptidase (NEP); however, the P2' beta-Ala derivative 6c uniquely inhibited HBSM ECE much more potently than NEP.

Aspartic Acid Endopeptidases↗
PubMed2002

Deactivation of P-glycoprotein by a novel compound, oxalyl bis (N-phenyl) hydroxamic acid.

A plasma membrane glycoprotein (P-gp) of 170 kd is over-expressed in most of the drug resistant cells. P-gp is encoded in humans by the gene mdrl and is thought to function as a broad substrate ATP-dependent drug efflux pump. P-gp is also present in many types of normal cells. A good number of chemicals inhibit or deactivate P-gp and thus reverse multidrug resistance (MDR). Most of the reported resistance modifying agents (RMAs) are effective in vitro and have adverse effect on the hosts. Hence, the development of nontoxic RMA is of immense importance in the field of cancer chemotherapy. With this end in view, a nontoxic resistance modifying agent, viz., oxalyl bis (N-phenyl) hydroxamic acid (OPHA) has been developed on the basis of the structural commonalities of the reported RMAs. We reported earlier that OPHA reverses doxorubicin resistance in vitro and also reduces glutathione and glutathione S-transferase in a non P-gp expressing cell line. In the present report, the inhibition of P-gp by the compound, OPHA in human cervical cancer cell line, HeLa, has been described by western blotting, study of immunofluorescence and enzyme linked immunofluorescence assay (ELISA). The inhibition of P-gp by OPHA is significantly higher than that of verapamil. The high IC50 values of OPHA against different cell lines indicate the non toxic nature of the compound. This work underscores the possibility of using the present hydroxamic acid derivative as the nontoxic modulator of the MDR phenotype.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Sulfonamide-based hydroxamic acids as potent inhibitors of mouse macrophage metalloelastase.

The structural requirements of sulfonamide-based hydroxamic acid 1 for inhibition of macrophage metalloelastase (MME) were investigated. A short aliphatic group at the R2 position together with an aromatic group at the R3 position significantly improved the inhibitory activity. Compounds 32, 34, and 40 were the most potent inhibitors of MME with IC50 values between 5 and 6 nM.

Animals↗